For many drugs, a key hurdle to effective oral delivery is the "first pass" effect. See GOODMAN AND GILMANS: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, pages 5 and 15 (Macmillan Publishing Co. 1985) ("Goodman and Gilman's"). Upon oral administration, a pharmaceutical agent is taken up by the lumen of the stomach and enters the portal vein. The portal vein delivers this agent to the liver before it is passed to the rest of the body. On this first pass, high levels of catabolic enzymes in the liver results in significant metabolism of the drug before it can reach its intended site of action, thereby increasing the amount of drug required for efficacious treatment.
Methylxanthines define a category of pharmaceutical agents substantially affected by the first pass effect. Illustrative of the methylxanthines are caffeine, theophylline, theobromine, aminofylline, pentoxifylline, and lisofylline, (R)-1-(5-hydroxyhexyl)-3,5-dimethylxanthine (LSF). Methylxanthines are important therapeutic compounds, useful in treating a wide variety of clinical indications. See Goodman and Gilman's at pages 589-603, for example, as well as U.S. Pat. No. 3,422,307, U.S. Pat. No. 3,737,433, U.S. Pat. No. 4,515,795, U.S. Pat. No. 4,576,947, U.S. Pat. No. 4,636,507, U.S. Pat. No. 4,833,146, U.S. Pat. No. 4,965,271, U.S. Pat. No. 5,039,666, and U.S. Pat. No. 5,096,906.
Although Methylxanthines are absorbed quickly and efficiently via oral, rectal and parenteral routes, they are significantly metabolized by liver enzymes. This metabolism results in decreased circulating drug levels and, hence, decreasing bioavailability. In practical terms, therefore, larger quantities of drug must be administered to the patient, raising cost concerns and the possibility of accumulating toxic metabolites.
The cytochrome P-450 superfamily of isozymes serves a predominant role in hepatic drug metabolism. They have been implicated in the metabolism of a significant number of divergent bioactive compounds, including methylxanthines. Yang et al., "The diversity of substrates for cytochrome P-450" in II MAMMALIAN CYTOCHROME P-450 2-17 (CRC Press 1987). Given the number and highly variable specificities of the P-450 isozymes, however, it is nearly impossible to predict which isoform is responsible for the metabolism of a particular compound. Even if the particular responsible isozyme were known, moreover, no methods currently exist for rationally designing effective inhibitors of enzymes with such substrate specificity.
Accordingly, an unmet need exists for compounds and methods that inhibit the metabolism of target pharmaceutical agents during treatment. In particular, there is a substantial need for compounds and methods that can be used to modulate cellular P-450 metabolism and, thereby influence, and specifically increase, circulating levels of such pharmaceuticals. The need is especially acute for compounds and methods that provide for higher circulating levels of methylxanthines.